Benzimidazoles useful as modulators of ion channels

ABSTRACT

The present invention relates to compounds of Formula I: 
                         
or a pharmaceutically acceptable salt thereof, wherein the R 1 , Z, Y, R A , and W groups of formula I are as defined herein. The invention also provides pharmaceutically acceptable compositions and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/977,609, filed Oct. 28, 2004, now U.S. Pat. No. 7,309,716 titled“BENZIMIDAZOLES USEFUL AS MODULATORS OF ION CHANNELS,” which claims thebenefit under 35 U.S.C. §119(e) of U.S. provisional application Ser. No.60/515,088, titled “COMPOSITIONS USEFUL AS INHIBITORS OF VOLTAGE-GATEDSODIUM CHANNELS,” filed Oct. 28, 2003, the entire contents of eachapplication being incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofvoltage-gated sodium channels. The invention also providespharmaceutically acceptable compositions comprising the compounds of theinvention and methods of using the compositions in the treatment ofvarious disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12 (1): 85-91)),pain (See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channelsand pain” Proc Natl Acad Sci USA 96 (14): 7635-9 and Waxman, S. G., T.R. Cummins, et al. (2000) “Voltage-gated sodium channels and themolecular pathogenesis of pain: a review” J Rehabil Res Dev 37 (5):517-28), myotonia (See, Meola, G. and V. Sansone (2000) “Therapy inmyotonic disorders and in muscle channelopathies” Neurol Sci 21 (5):S953-61 and Mankodi, A. and C. A. Thornton (2002) “Myotonic syndromes”Curr Opin Neurol 15 (5): 545-52), ataxia (See, Meisler, M. H., J. A.Kearney, et al. (2002) “Mutations of voltage-gated sodium channels inmovement disorders and epilepsy” Novartis Found Symp 241: 72-81),multiple sclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000)“Sensory neuron-specific sodium channel SNS is abnormally expressed inthe brains of mice with experimental allergic encephalomyelitis andhumans with multiple sclerosis” Proc Natl Acad Sci USA 97 (21):11598-602, and Renganathan, M., M. Gelderblom, et al. (2003) “Expressionof Na(v)1.8 sodium channels perturbs the firing patterns of cerebellarpurkinje cells” Brain Res 959 (2): 235-42), irritable bowel (See, Su,X., R. E. Wachtel, et al. (1999) “Capsaicin sensitivity andvoltage-gated sodium currents in colon sensory neurons from rat dorsalroot ganglia” Am J Physiol 277 (6 Pt 1): G1180-8, and Laird, J. M., V.Souslova, et al. (2002) “Deficits in visceral pain and referredhyperalgesia in Nav1.8 (SNS/PN3)-null mice” J Neurosci 22 (19): 8352-6),urinary incontinence and visceral pain (See, Yoshimura, N., S. Seki, etal. (2001) “The involvement of the tetrodotoxin-resistant sodium channelNa(v)1.8 (PN3/SNS) in a rat model of visceral pain” J Neurosci 21 (21):8690-6), as well as an array of psychiatry dysfunctions such as anxietyand depression (See, Hurley, S. C. (2002) “Lamotrigine update and itsuse in mood disorders” Ann Pharmacother 36 (5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See, Noda, M., H. Suzuki, et al. (1989) “A single pointmutation confers tetrodotoxin and saxitoxin insensitivity on the sodiumchannel II” FEBS Lett 259 (1): 213-6).

Table 1 (Abbreviations: CNS=central nervous system, PNS=peripheralnervous system, DRG=dorsal root ganglion, TG=Trigeminal ganglion):

Na isoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain,Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nMNeurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic,injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μMArrythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread,most abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminalsdisorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG &TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87 (1): 7-17) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59 (5 Suppl 2): S14-7), have been shown tobe useful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256 (1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2 (6): 541-8). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379 (6562): 257-62). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell,et al. (1999) “Plasticity of sodium channel expression in DRG neurons inthe chronic constriction injury model of neuropathic pain.” Pain 83 (3):591-600). The timecourse of the increase in NaV1.3 parallels theappearance of allodynia in animal models subsequent to nerve injury. Thebiophysics of the NaV1.3 channel is distinctive in that it shows veryfast repriming after inactivation following an action potential. Thisallows for sustained rates of high firing as is often seen in theinjured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3sodium channels: rapid repriming and slow closed-state inactivationdisplay quantitative differences after expression in a mammalian cellline and in spinal sensory neurons” J Neurosci 21 (16): 5952-61). NaV1.3is expressed in the central and peripheral systems of man. NaV1.9 issimilar to NaV1.8 as it is selectively localized to small sensoryneurons of the dorsal root ganglion and trigeminal ganglion (See, Fang,X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22 (17): 7425-33). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25 (5): 253-9). Thesetwo biophysical properties allow NaV1.9 to play a role in establishingthe resting membrane potential of nociceptive neurons. The restingmembrane potential of NaV1.9 expressing cells is in the −55 to −50 mVrange compared to −65 mV for most other peripheral and central neurons.This persistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli. In chronic pain states, nerve and nerveending can become swollen and hypersensitive exhibiting high frequencyaction potential firing with mild or even no stimulation. Thesepathologic nerve swellings are termed neuromas and the primary Nachannels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T.,L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channelsin painful human neuroma-evidence from immunocytochemistry” ActaNeurochir (Wien) 144 (8): 803-10; discussion 810). NaV1.6 and NaV1.7 arealso expressed in dorsal root ganglion neurons and contribute to thesmall TTX sensitive component seen in these cells. NaV1.7 in particularmy therefore be a potential pain target in addition to it's role inneuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al.(1995) “Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells” Embo J 14 (6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57 (4): 703-5) and NaV1.2 (See, Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alphaII subunit gene Na(v) 1.2 in a patient with febrile and afebrileseizures causes channel dysfunction” Proc Natl Acad Sci USA 98 (11):6384-9) have been linked to epilepsy conditions including febrileseizures. There are over 9 genetic mutations in NaV1.1 associated withfebrile seizures (See, Meisler, M. H., J. A. Kearney, et al. (2002)“Mutations of voltage-gated sodium channels in movement disorders andepilepsy” Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99 (7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21 (9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96 (14): 7645-9), and neuropathicpain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46 (10): 1261-4); cardiac arrhythmias (See, An, R.H., R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant humanNa+ channels” Circ Res 79 (1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99 (7): 1714-20); neuroprotection (See, Taylor, C. P. and L.S. Narasimhan (1997) “Sodium channels and therapy of central nervoussystem diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See,Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations oflocal anaesthetics unveil the potential role of sodium channels inneuropathic pain.” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed forthe study of sodium channel modulators for numerous different painindications. E.g., malignant chronic pain, see, Kohase, H., et al., ActaAnaesthesiol Scand. 2004; 48 (3):382-3; femur cancer pain (see, Kohase,H., et al., Acta Anaesthesiol Scand. 2004; 48 (3):382-3); non-malignantchronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994; 42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav BrainRes. 1987; 24 (1):11-29); osteoarthritis (see, Guzman, R. E., et al.,Toxicol Pathol. 2003; 31 (6):619-24); spinal stenosis (see, Takenobu, Y.et al., J Neurosci Methods. 2001; 104 (2):191-8); Neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3 (4):361-5; Massie, J.B., et al., J Neurosci Methods. 2004; 137 (2):283-9; neuropathic lowback pain (see, Hines, R., et al., Pain Med. 2002; 3 (4):361-5; Massie,J. B., et al., J Neurosci Methods. 2004; 137 (2):283-9); myofascial painsyndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002;16 (1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24 (1):37-46);fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995; 15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain ResMol Brain Res. 1999; 67 (1):87-97); chronic visceral pain, including,abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000; 119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., NeurosciLett. 1998; 246 (2):73-6); pancreatic (see, Vera-Portocarrero, L. B., etal., Anesthesiology. 2003; 98 (2):474-84); IBS pain (see, Verne, G. N.,et al., Pain. 2003; 105 (1-2):223-30; La J H et al., WorldGastroenterol. 2003; 9 (12):2791-5); chronic headache pain (see,Willimas & Stark, Cephalalgia. 2003; 23 (10):963-71); migraine (see,Yamamura, H., et al., J Neurophysiol. 1999; 81 (2):479-93); tensionheadache, including, cluster headaches (see, Costa, A., et al.,Cephalalgia. 2000; 20 (2):85-91); chronic neuropathic pain, including,post-herpetic neuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355); diabetic neuropathy (see,Beidoun A et al., Clin J Pain. 2004; 20 (3):174-8; Courteix, C., et al.,Pain. 1993; 53 (1):81-8); HIV-associated neuropathy (see, Portegies &Rosenberg, Ned Tijdschr Geneeskd. 2001; 145 (15):731-5; Joseph E K etal., Pain. 2004; 107 (1-2):147-58; Oh, S. B., et al., J Neurosci. 2001;21 (14):5027-35); trigeminal neuralgia (see, Sato, J., et al., Oral SurgOral Med Oral Pathol Oral Radiol Endod. 2004; 97 (1):18-22; Imamura Y etal., Exp Brain Res. 1997; 116 (1):97-103); Charcot-Marie Toothneuropathy (see, Sereda, M., et al., Neuron. 1996; 16 (5):1049-60);hereditary sensory neuropathies (see, Lee, M. J., et al., Hum Mol Genet.2003; 12 (15):1917-25); peripheral nerve injury (see, Attal, N., et al.,Neurology. 2004; 62 (2):218-25; Kim & Chung 1992, Pain 50:355; Bennett &Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149;Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas(see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46 (1):15-22; Devor &Raber, Behav Neural Biol. 1983; 37 (2):276-83); ectopic proximal anddistal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27); radiculopathy (see, Devers & Galer, (see, Clin J Pain.2000; 16 (3):205-8; Hayashi N et al., Spine. 1998; 23 (8):877-85);chemotherapy induced neuropathic pain (see, Aley, K. O., et al.,Neuroscience. 1996; 73 (1):259-65); radiotherapy-induced neuropathicpain; post-mastectomy pain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain (Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cord injury pain (see, Hains, B. C., et al., ExpNeurol. 2000; 164 (2):426-37); post-stroke pain; thalamic pain (see,LaBuda, C. J., et al., Neurosci Lett. 2000; 290 (1):79-83); complexregional pain syndrome (see, Wallace, M. S., et al., Anesthesiology.2000; 92 (1):75-83; Xantos D et al., J Pain. 2004; 5 (3 Suppl 2):S1);phantom pain (see, Weber, W. E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain. 1981; 10 (1):67-73); intractablepain (see, Yokoyama, M., et al., Can J Anaesth. 2002; 49 (8):810-3);acute pain, acute post-operative pain (see, Koppert, W., et al., AnesthAnalg. 2004; 98 (4):1050-5; Brennan, T. J., et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; joint pain (see, Gotoh, S., etal., Ann Rheum Dis. 1993; 52 (11):817-22); mechanical low back pain(see, Kehl, L. J., et al., Pain. 2000; 85 (3):333-43); neck pain;tendonitis; injury/exercise pain (see, Sesay, M., et al., Can J Anaesth.2002; 49 (2):137-43); acute visceral pain, including, abdominal pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; etc (see, Giambernardino, M. A., et al., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain (see, Vergona, R. A.,et al., Life Sci. 1984; 35 (18):1877-84); pelvic pain, renal colic pain,acute obstetric pain, including, labor pain (see, Segal, S., et al.,Anesth Analg. 1998; 87 (4):864-9); cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis (see, Cason, A. M., et al., Horm Behav. 2003; 44(2):123-31); acute herpes zoster pain; sickle cell anemia; acutepancreatitis (see, Toma, H; Gastroenterology. 2000; 119 (5):1373-81);breakthrough pain; orofacial pain, including, sinusitis pain, dentalpain (see, Nusstein, J., et al., J Endod. 1998; 24 (7):487-91; Chidiac,J. J., et al., Eur J Pain. 2002; 6 (1):55-67); multiple sclerosis (MS)pain (see, Sakurai & Kanazawa, J Neurol Sci. 1999; 162 (2):162-8); painin depression (see, Greene B, Curr Med Res Opin. 2003; 19 (4):272-7);leprosy pain; behcet's disease pain; adiposis dolorosa (see, Devillers &Oranje, Clin Exp Dermatol. 1999; 24 (3):240-1); phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain (see, Legroux-Crespel, E., et al., Ann DermatolVenereol. 2003; 130 (4):429-33); Fabry's disease pain (see, Germain, D.P., J Soc Biol. 2002; 196 (2):183-90); Bladder and urogenital disease,including, urinary incontinence (see, Berggren, T., et al., J Urol.1993; 150 (5 Pt 1):1540-3); hyperactivity bladder (see, Chuang, Y. C.,et al., Urology. 2003; 61 (3):664-70); painful bladder syndrome (see,Yoshimura, N., et al., J Neurosci. 2001; 21 (21):8690-6); interstitialcyctitis (IC) (see, Giannakopoulos & Campilomatos, Arch Ital Urol NefrolAndrol. 1992; 64 (4):337-9; Boucher, M., et al., J Urol. 2000; 164(1):203-8); and prostatitis (see, Mayersak, J. S., Int Surg. 1998; 83(4):347-9; Keith, I. M., et al., J Urol. 2001; 166 (1):323-8).

Voltage-gated calcium channels are membrane-spanning, multi-subunitproteins that open in response to membrane depolarization, allowing Caentry from the extracellular milieu. Calcium channels were initiallyclassified based on the time and voltage-dependence of channel openingand on the sensitivity to pharmacological block. The categories werelow-voltage activated (primarily T-type) and high-voltage activated (L,N, P, Q or R-type). This classification scheme was replaced by anomenclature based upon the molecular subunit composition, as summarizedin Table I (Hockerman, G. H., et. al. (1997) Annu. Rev. Pharmacol.Toxicol. 37: 361-96; Striessnig, J. (1999) Cell. Physiol. Biochem. 9:242-69). There are four primary subunit types that make up calciumchannels—α₁, α₂δ, β and γ (See, e.g., De Waard et al. Structural andfunctional diversity of voltage-activated calcium channels. In IonChannels, (ed. T. Narahashi) 41-87, (Plenum Press, New York, 1996)). Theα₁ subunit is the primary determinant of the pharmacological propertiesand contains the channel pore and voltage sensor (Hockerman, G. H., et.al. (1997) Annu. Rev. Pharmacol. Toxicol. 37: 361-96; Striessnig, J.(1999) Cell. Physiol. Biochem. 9: 242-69). Ten isoforms of the α₁subunit are known, as indicated in Table I. The α₂δ subunit consists oftwo disulfide linked subunits, α₂, which is primarily extracellular anda transmembrane δ subunit. Four isoforms of α₂δ are known, α₂δ-1, α₂δ-2,α₂δ-3 and α₂δ-4. The β subunit is a non-glycosylated cytoplasmic proteinthat binds to the α₁ subunit. Four isoforms are known, termed β₁ to β₄.The γ subunit is a transmembrane protein that has been biochemicallyisolated as a component of Ca_(v)1 and Ca_(v)2 channels. At least 8isoforms are known (γ₁ to γ₈) (Kang, M. G. and K. P. Campbell (2003) J.Biol. Chem. 278: 21315-8). The nomenclature for voltage-gated calciumchannels is based upon the content of the α₁ subunit, as indicated inTable I. Each type of α₁ subunit can associate with a variety of β, α₂δor γ subunits, so that each Ca_(v) type corresponds to many differentcombinations of subunits.

Cav Nomenclature α₁ subunit Pharmacological name Ca_(v)1.1 α_(1S) L-typeCa_(v)1.2 α_(1C) L-type Ca_(v)1.3 α_(1D) L-type Ca_(v)1.4 α_(1F)Ca_(v)2.1 α_(1A) P- or Q-type Ca_(v)2.2 α_(1B) N-type Ca_(v)2.3 α_(1E)R-type Ca_(v)3.1 α_(1G) T-type Ca_(v)3.2 α_(1H) T-type Ca_(v)3.3 α_(1I)T-type

Ca_(v)2 currents are found almost exclusively in the central andperipheral nervous system and in neuroendocrine cells and constitute thepredominant forms of presynaptic voltage-gated calcium current.Presynaptic action potentials cause channel opening and neurotransmitterrelease is steeply dependent upon the subsequent calcium entry. Thus,Ca_(v)2 channels play a central role in mediating neurotransmitterrelease.

Ca_(v)2.1 and Ca_(v)2.2 contain high affinity binding sites for thepeptide toxins □-conotoxin-MVIIC and □-conotoxin-GVIA, respectively, andthese peptides have been used to determine the distribution and functionof each channel type. Ca_(V)2.2 is highly expressed at the presynapticnerve terminals of neurons from the dorsal root ganglion and neurons oflamina I and II of the dorsal horn (Westenbroek, R. E., et al. (1998) J.Neurosci. 18: 6319-30; Cizkova, D, et al. (2002) Exp. Brain Res. 147:456-63). Ca_(V)2.2 channels are also found in presynaptic terminalsbetween second and third order interneurons in the spinal cord. Bothsites of neurotransmission are very important in relaying paininformation to the brain.

Pain can be roughly divided into three different types: acute,inflammatory, and neuropathic. Acute pain serves an important protectivefunction in keeping the organism safe from stimuli that may producetissue damage. Severe thermal, mechanical, or chemical inputs have thepotential to cause severe damage to the organism if unheeded. Acute painserves to quickly remove the individual from the damaging environment.Acute pain by its very nature generally is short lasting and intense.Inflammatory pain, on the other hand, may last for much longer periodsof time and its intensity is more graded. Inflammation may occur formany reasons including tissue damage, autoimmune response, and pathogeninvasion. Inflammatory pain is mediated by a variety of agents that arereleased during inflammation, including substance P, histamines, acid,prostaglandin, bradykinin, CGRP, cytokines, ATP, and other agents(Julius, D. and A. I. Basbaum (2001) Nature 413 (6852): 203-10). Thethird class of pain is neuropathic and involves nerve damage arisingfrom nerve injury or viral infection and results in reorganization ofneuronal proteins and circuits yielding a pathologic “sensitized” statethat can produce chronic pain lasting for years. This type of painprovides no adaptive benefit and is particularly difficult to treat withexisting therapies.

Pain, particularly neuropathic and intractable pain is a large unmetmedical need. Millions of individuals suffer from severe pain that isnot well controlled by current therapeutics. The current drugs used totreat pain include NSAIDS, COX-2 inhibitors, opioids, tricyclicantidepressants, and anticonvulsants. Neuropathic pain has beenparticularly difficult to treat as it does not respond well to opioidsuntil high doses are reached. Gabapentin is currently the most widelyused therapeutic for the treatment of neuropathic pain, although itworks in only 60% of patients and has modest efficacy. The drug isgenerally safe, although sedation is an issue at higher doses.

Validation of Cav2.2 as a target for the treatment of neuropathic painis provided by studies with ziconotide (also known as□-conotoxin-MVIIA), a selective peptide blocker of this channel(Bowersox, S. S., et al. (1996) J. Pharmacol. Exp. Ther. 279: 1243-9;Jain, K. K. (2000) Exp. Opin. Invest. Drugs 9: 2403-10; Vanegas, H. andH. Schaible (2000) Pain 85: 9-18). In man, intrathecal infusion ofZiconotide is effective for the treatment of intractable pain, cancerpain, opioid resistant pain, and neuropathic pain. The toxin has an 85%success rate for the treatment of pain in humans with a greater potencythan morphine. An orally available antagonist of Ca_(V)2.2 should havesimilar efficacy without the need for intrathecal infusion. Ca_(V)2.1and Ca_(V)2.3 are also in neurons of nociceptive pathways andantagonists of these channels could be used to treat pain.

Antagonists of Ca_(V)2.1, Ca_(V)2.2 or Ca_(V)2.3 should also be usefulfor treating other pathologies of the central nervous system thatapparently involve excessive calcium entry. Cerebral ischaemia andstroke are associated with excessive calcium entry due to depolarizationof neurons. The Ca_(V)2.2 antagonist ziconotide is effective in reducinginfarct size in a focal ischemia model using laboratory animals,suggesting that Ca_(V)2.2 antagonists could be used for the treatment ofstroke. Likewise, reducing excessive calcium influx into neurons may beuseful for the treatment of epilepsy, traumatic brain injury,Alzheimer's disease, multi-infarct dementia and other classes ofdementia, amyotrophic lateral sclerosis, amnesia, or neuronal damagecaused by poison or other toxic substances.

Ca_(V)2.2 also mediates release of neurotransmitters from neurons of thesympathetic nervous system and antagonists could be used to treatcardiovascular diseases such as hypertension, cardiac arrhythmia, anginapectoris, myocardial infarction, and congestive heart failure.

However, as described above, the efficacy of currently used sodiumchannel blockers and calcium channel blockers for the disease statesdescribed above has been to a large extent limited by a number of sideeffects. These side effects include various CNS disturbances such asblurred vision, dizziness, nausea, and sedation as well more potentiallylife threatening cardiac arrhythmias and cardiac failure. Accordingly,there remains a need to develop additional Na channel antagonists, andCa channel antagonists preferably those with higher potency and fewerside effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thestructure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R^(A), Z, Y, r,and W are as defined below.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain such as femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; neuropathic low back pain;myofascial pain syndrome; fibromyalgia; temporomandibular joint pain;chronic visceral pain, including, abdominal; pancreatic; IBS pain;chronic headache pain; migraine; tension headache, including, clusterheadaches; chronic neuropathic pain, including, post-herpetic neuralgia;diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas;

ectopic proximal and distal discharges; radiculopathy; chemotherapyinduced neuropathic pain; radiotherapy-induced neuropathic pain;post-mastectomy pain; central pain; spinal cord injury pain; post-strokepain; thalamic pain; complex regional pain syndrome; phantom pain;intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury/exercise pain; acute visceral pain, including,abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinalobstruction; hernias; etc; chest pain, including, cardiac Pain; pelvicpain, renal colic pain, acute obstetric pain, including, labor pain;cesarean section pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, including, endometriosis; acute herpes zoster pain;sickle cell anemia; acute pancreatitis; breakthrough pain; orofacialpain, including, sinusitis pain, dental pain; multiple sclerosis (MS)pain; pain in depression; leprosy pain; behcet's disease pain; adiposisdolorosa; phlebitic pain; Guillain-Barre pain; painful legs and movingtoes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain;bladder and urogenital disease, including, urinary incontinence;hyperactivity bladder; painful bladder syndrome; interstitial cyctitis(IC); or prostatitis, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description ofCompounds of the Invention

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   r is 0 to 4;-   Z is O, N or CH;-   Y and W are independently selected from hydrogen, Formula Ia:

-   -   wherein:

-   -   A is -T-NH—,        -   wherein:            -   T is a bond or a C₁₋₆ straight or branched aliphatic                chain wherein a methylene unit of T is optionally                replaced by a C₃₋₈ cycloaliphatic group;            -   U is —CH₂— or —CH₂—CH₂—;            -   X is N—C₁₋₄alkyl, NH, O, S, S(O), or SO₂; and            -   each occurrence of R^(C) is independently M-R^(X);                wherein:                -   M is a bond or is a C₁₋₆ alkylidene chain wherein up                    to two non-adjacent methylene units of M are                    optionally replaced by C(O), CO₂, C(O)C(O), C(O)NR,                    OC(O)NR, NRNR, NRNRC(O), NRC(O), NRCO₂, NRC(O)NR,                    S(O), SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR, and                -   R^(X) is R′, halogen, NO₂, or CN; wherein:                -    each occurrence of R′ is independently selected                    from hydrogen or an optionally substituted group                    selected from C₁₋₈ aliphatic, C₆₋₁₀ aryl, a                    heteroaryl ring having 5-10 ring atoms, or a                    heterocyclyl ring having 3-10 ring atoms, or R and                    R′ taken together with the atom(s) to which they are                    bound, or two occurrences of R′ taken together with                    the atom(s) to which they are bound, form a 5-8                    membered cycloalkyl, heterocyclyl, aryl, or                    heteroaryl ring having 0-3 heteroatoms independently                    selected from nitrogen, oxygen, or sulfur;    -   V is a bond, —C(O)—, or —S(O)₂—;    -   Q is a bond or a C₁₋₄ alkylidene chain wherein up to two        non-adjacent methylene units of Q are optionally replaced by        —O—, —NH—, or —S—;    -   m is 0 or 1;    -   Ring E is C₆₋₁₀ aryl, a 5-10 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or a 3-10 membered heterocyclyl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   s is 0 to 8;

-   or Formula Ib:

-   -   wherein:    -   D is —C₁₋₆alkyl- or a bond; and    -   t is 0 to 5;

-   each occurrence of R is independently selected from hydrogen or an    optionally substituted C₁₋₆ aliphatic group; and

-   each occurrence of R^(A), R^(B) and R^(D) are independently selected    from R¹, R², R³, R⁴, or R⁵, wherein:    -   R¹ is oxo, R⁶ or (C₁₋₄aliphatic)_(n)-J, wherein:        -   n is 0 or 1;        -   J is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂,            NHR⁶, N(R⁶)₂, NR⁶R⁸, C(O)OH, C(O)OR⁶ or OR⁶; or:        -   two R¹ on adjacent ring atoms, taken together, form            1,2-methylenedioxy or 1,2-ethylenedioxy;    -   R² is C₁₋₆aliphatic, optionally substituted with up to two        substituents independently selected from R¹, R⁴, or R⁵;    -   R³ is C₃₋₈cycloaliphatic, C₆₋₁₀ aryl, a 5-10 membered heteroaryl        ring having 1-4 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or a 3-10 membered heterocyclyl        ring having 1-4 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, wherein R³ is optionally        substituted with up to three substituents independently selected        from R¹, R², R⁴ or R⁵;    -   R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵,        OC(O)N(R⁶)₂, OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), SR⁶, SR⁵, S(O)R⁶,        S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶, SO₃R⁶,        SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂,        C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵,        C(O)N(OR⁵)R⁵, C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵,        N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶), NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵,        NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵, NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂,        NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶,        NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂,        NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶,        N(OR⁶)R⁵, N(OR⁵)R⁵, or N(OR⁵)R⁶;    -   R⁵ is a C₃₋₈cycloaliphatic, C₆₋₁₀ aryl, a 5-10 membered        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, or a 3-10 membered        heterocyclyl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, wherein R⁵ is optionally        substituted with up to three R¹ substituents;    -   R⁶ is R optionally substituted with R⁷, wherein:        -   R⁷ is a C₃₋₈cycloaliphatic, C₆₋₁₀ aryl, a 5-10 membered            heteroaryl ring having 1-4 heteroatoms independently            selected from nitrogen, oxygen, or sulfur, or a 3-10            membered heterocyclyl ring having 1-4 heteroatoms            independently selected from nitrogen, oxygen, or sulfur,            wherein R⁷ is optionally substituted with up to two            substituents independently selected from R,            1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH₂)_(n)-G,            wherein G is selected from halo, CN, NO₂, CF₃, OCF₃, OH,            S-aliphatic, S(O)-aliphatic, SO₂-aliphatic, NH₂,            N-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH,            C(O)O(-aliphatic, or O-aliphatic; and    -   R⁸ is an amino protecting group;        provided that only one of Y and W is formula Ia or Ib and the        other of Y and W is hydrogen.

In certain other embodiments, for compounds of Formula I as describedgenerally above and herein:

-   -   a) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        Q is —C₁alkyl-O—, and Ring E is phenyl, then R^(A) is not        hydrogen, —Cl, —Br, C₁₋₄alkyl, methoxy, or nitro, either singly        or in combination;    -   b) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        Q is a bond, and Ring E is phenyl, then R^(A) is not hydrogen,        —Cl, —Br, C₁₋₄alkyl, methoxy, or nitro, either singly or in        combination;    -   c) when Z is N, W is Formula Ia, A is —C₃alkyl-NH—, V is —C(O)—,        Q is a bond, and Ring E is phenyl, then R^(A) is not 4-amino, or        4-methoxycarbonyl;    -   d) when Z is N, W is Formula Ia, A is —C₃alkyl-NH—, V is —C(O)—,        and Q is a bond, then Ring E is not        -2(2,3-dihydro-benzo[1,4]dioxine);    -   e) when Z is N, W is Formula Ia, A is —C₃alkyl-NH—, V is —C(O)—,        and Q is a —C₁alkyl-O—, then Ring E is not        -6(4-dimethyl-2H-chromen-2-one);    -   f) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        and Q is a —C₂alkyl-O—, then Ring E is not unsubstituted phenyl;    -   g) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        and B is a bond, then Ring E is not unsubstituted thienyl;    -   h) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        and Q is a —C₁alkyl-O—, and Ring E is phenyl, then R^(A) is not        phenyl at the 4 position;    -   i) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        and Q is a —C₂alkyl, then Ring E is not 2-isoindoline-1,3-dione;    -   j) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        and Q is a —C₂alkyl-O—, and Ring E is phenyl, then R^(A) is not        phenyl at the 4 position; and    -   k) when Z is N, W is Formula Ia, A is —C₂alkyl-NH—, V is —C(O)—,        and Q is a bond, then Ring E is not unsubstituted adamantyl.

According to another embodiment, the present invention provides acompound of formula Ia, as defined generally above, wherein:

-   (a) when Z is N, Y is hydrogen, W is formula Ia, A is

-    and V and Q are each a bond, then:    -   (i) when r is 1 and R^(A) is methyl in the C-5 or C-6 position        of the benzimidazole ring, then E is not:        -   unsubstituted phenyl;        -   phenyl substituted in the ortho position with methyl, OMe,            or OEt; or        -   phenyl substituted in the para position with OMe or methyl;            and    -   (ii) when r is 0, then E is not:        -   unsubstituted phenyl;        -   unsubstituted naphthyl;        -   phenyl substituted in the para position with OEt, Br, OH, or            OMe;        -   phenyl substituted in the meta position with chloro; or        -   phenyl substituted in the ortho position with methyl;-   (b) when Z is N, Y is hydrogen, W is formula Ia, Q is —NHCH₂—, r is    0, and V is C(O), then:    -   (i) when A is —CH₂CH₂NH—, then E is not

-   -   (ii) when A is —CH₂NH—, then E is not

-   (c) when Z is C, W is hydrogen, Y is formula Ia, r is 0, A is    —CH₂CH₂NH—, V is C(O), Q is —CH₂O— and E is phenyl, then:    -   (i) s is not 0;    -   (ii) when s is 1, R^(B) is not:        -   unsubstituted phenyl, chloro, OMe, methyl, bromo,

-   -   -    or

-   -   -    in the para position;        -   cyano or OMe in the ortho position; or        -   methyl in the meta position;

    -   (iii) when s is 2, R^(B) is not dichloro in the ortho/para        positions; and

    -   (iv) when s is 3, R^(B) is not 2,3,4-trimethoxy or        2,4,5-trichloro.

In certain other embodiments, for compounds of Formula I as describedgenerally above and herein:

-   -   a) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—, Q        is —CH₂O—, and Ring E is phenyl, then R^(A) is not —Cl, —Br,        C₁₋₄alkyl, methoxy, or nitro, either singly or in combination;    -   b) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—, Q        is a bond, and Ring E is phenyl, then R^(A) is not —Cl, —Br,        C₁₋₄alkyl, methoxy, or nitro, either singly or in combination;    -   c) when Z is N, W is Formula Ia, A is —CH₂CH₂CH₂NH—, V is        —C(O)—, Q is a bond, and Ring E is phenyl, then R^(A) is not        4-amino, or 4-methoxycarbonyl;    -   d) when Z is N, W is Formula Ia, A is —CH₂CH₂CH₂NH—, V is        —C(O)—, and Q is a bond, then Ring E is not        -2(2,3-dihydro-benzo[1,4]dioxine);    -   e) when Z is N, W is Formula Ia, A is —CH₂CH₂CH₂NH—, V is        —C(O)—, and Q is a —CH₂O—, then Ring E is not        -6(4-dimethyl-2H-chromen-2-one);    -   f) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—,        and Q is a —CH₂CH₂O—, then Ring E is not unsubstituted phenyl;    -   g) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—,        and Q is a bond, then Ring E is not unsubstituted thienyl;    -   h) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—,        and Q is a —CH₂O—, and Ring E is phenyl, then R^(A) is not        phenyl at the 4 position;    -   i) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—,        and Q is —CH₂CH₂—, then Ring E is not 2-isoindoline-1,3-dione;    -   j) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—,        and Q is —CH₂CH₂O—, and Ring E is phenyl, then R^(A) is not        phenyl at the 4 position; and    -   k) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—,        and Q is a bond, then Ring E is not unsubstituted adamantyl.    -   l) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—, Q        is —CH₂CH₂O—, and Ring E is phenyl, then R^(B) is not —Cl, —Br,        C₁₋₄alkyl, methoxy, unsubstituted phenyl, —C(CH₃)₂phenyl, or        nitro, either singly or in combination;    -   m) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —C(O)—, Q        is —CH═CH₂—, and Ring E is phenyl, then R^(B) is not —Cl in the        ortho position; and    -   n) when Z is N, W is Formula Ia, A is —CH₂CH₂NH—, V is —SO₂—, Q        is a bond, and Ring E is phenyl, then R^(B) is not chloro.

Another embodiment of the present invention provides a method oftreating or lessening the severity of a disease, disorder, or conditionselected from acute, chronic, neuropathic, or inflammatory pain,including femur cancer pain; non-malignant chronic bone pain; rheumatoidarthritis; osteoarthritis; spinal stenosis; neuropathic low back pain;neuropathic low back pain; myofascial pain syndrome; fibromyalgia;temporomandibular joint pain; chronic visceral pain, including,abdominal; pancreatic; IBS pain; chronic headache pain; migraine;tension headache, including, cluster headaches; chronic neuropathicpain, including, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Toothneuropathy; hereditary sensory neuropathies; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury/exercise pain; acute visceral pain, including,abdominal pain; pyelonephritis; appendicitis; cholecystitis; intestinalobstruction; hernias; etc; chest pain, including, cardiac Pain; pelvicpain, renal colic pain, acute obstetric pain, including, labor pain;cesarean section pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, including, endometriosis; acute herpes zoster pain;sickle cell anemia; acute pancreatitis; breakthrough pain; orofacialpain, including, sinusitis pain, dental pain; multiple sclerosis (MS)pain; pain in depression; leprosy pain; behcet's disease pain; adiposisdolorosa; phlebitic pain; Guillain-Barre pain; painful legs and movingtoes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain;bladder and urogenital disease, including, urinary incontinence;hyperactivity bladder; painful bladder syndrome; interstitial cyctitis(IC); or prostatitis; arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or anepilepsy condition, a neurodegenerative disorder, a psychiatric disordersuch as anxiety and depression, myotonia, arrhythmia, a movementdisorder, a neuroendocrine disorder, ataxia, multiple sclerosis,irritable bowel syndrome, or incontinence comprising the step ofadministering to said patient an effective amount of a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein R^(A), Z, Y, r,and W are as defined above and in classes and subclasses as describedherein.

A preferred aspect of the present embodiment is where the disease,condition, or disorder is acute, chronic, neuropathic, or inflammatorypain.

Another embodiment of the present invention provides a method fortreating or lessening the severity of a disease, condition or disorderwherein the disease, condition, or disorder is implicated in theactivation of voltage-gated sodium channels comprising administering aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R^(A), Z, Y, r,and W are as defined above and in classes and subclasses as describedherein.

A preferred aspect of the present embodiment is where the disease,condition, or disorder is acute, chronic, neuropathic, or inflammatorypain, epilepsy or an epilepsy condition, a neurodegenerative disorder, apsychiatric disorder such as anxiety and depression, myotonia,arrhythmia, a movement disorder, a neuroendocrine disorder, ataxia,multiple sclerosis, irritable bowel syndrome, or incontinence.

A particularly preferred aspect of the present embodiment is where thedisease, condition, or disorder is acute, chronic, neuropathic, orinflammatory pain.

Another preferred aspect of the present embodiment is where the methodcomprises an additional therapeutic agent.

Yet another embodiment of the present invention provides a method ofinhibiting NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 activity in:

-   -   (a) a patient; or    -   (b) a biological sample;        which method comprises administering to said patient, or        contacting said biological sample with a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R^(A), Z, Y, r,and W are as defined above and in classes and subclasses as describedherein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The present invention provides compounds of Formula I with substituentsthat are monovalent, such as R^(A), R^(B), R^(C) and R^(D); or divalent,such as A, B, and D. Those skilled in the art will appreciate that forasymmetric divalent substituent groups, such as —C₁₋₆alkyl-NH—, and—C₁₋₄alkyl-O—, there are two possible orientations relative to theparent structure. As used within the present specification, theorientation of a divalent substituent is set by its left/rightorientation relative Formula I as taught in the present specification.Those skilled in the art will also appreciate that this orientationconvention is not relevant to symmetrical divalent substituents, such as—C(O)—, or —C₁₋₆alkyl-.

For example for Formula I, where Z is N, W is present as Ia, R^(A) ishydrogen, V is —C(O)—, Ring E is phenyl, R^(B) is hydrogen; and A and Qare divalent substituents (A is —C₃alkyl-NH—, and Q is —C₁alkyl-O—), thefollowing is the described compound.

For example for Formula I, where Z is N, W is present as Ia, R^(A) ishydrogen, V is —C(O)—, Ring E is phenyl, R^(B) is hydrogen; and A and Qare divalent substituents (A is —C₂alkyl-NH— and Q is —O—C₁alkyl-), thefollowing is the described compound.

For example for Formula I, where Z is N, W is present as Ia, U is —CH₂—,R^(A) is hydrogen, V is —C(O)—, Ring E is phenyl, R^(B) is hydrogen; andA and Q are divalent substituents (A is

and Q is —C₁alkyl-O—), the following is the described compound.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The terms “aliphatic”, “aliphatic group” or “alkyl” as used herein,means a straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms, i.e., C₁₋₂₀alkyl. In some embodiments, aliphatic groupscontain 1-10 aliphatic carbon atoms, i.e., C₁₋₁₀alkyl. In otherembodiments, aliphatic groups contain 1-8 aliphatic carbon atoms, i.e.,C₁₋₈alkyl. In still other embodiments, aliphatic groups contain 1-6aliphatic carbon atoms, i.e., C₁₋₆alkyl, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms, i.e., C₁₋₄alkyl. Insome embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”)refers to a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbonthat is completely saturated or that contains one or more units ofunsaturation, but which is not aromatic, that has a single point ofattachment to the rest of the molecule wherein any individual ring insaid bicyclic ring system has 3-7 members. Suitable aliphatic groupsinclude, but are not limited to, linear or branched, substituted orunsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, or “heterocyclic” as used herein meansnon-aromatic, monocyclic, bicyclic, or tricyclic ring systems in whichone or more ring members is an independently selected heteroatom. Insome embodiments, the “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, or “heterocyclic” group has three to fourteenring members in which one or more ring members is a heteroatomindependently selected from oxygen, sulfur, nitrogen, or phosphorus, andeach ring in the system contains 3 to 7 ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom, for exampleC₁₋₄alkoxy refers to the alkoxyl group, methoxy, ethyoxy, propoxy, andbutoxy, including for propoxy and butoxy, the straight and branchedstructures, that is i-propoxy and n-propoxy; and n-butoxy, i-butoxy andsec-butoxy.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl or heteroaryl group are selected fromhalogen; —R^(o); —OR^(o); —SR^(o); 1,2-methylene-dioxy;1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R^(o); —O(Ph)optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substitutedwith R^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(O)N(R^(o))₂; —NR^(o)CO₂R^(o);—NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(O)N(R^(o))₂; —OC(O)N(R^(o))₂; —S(O)₂R^(o); —SO₂N(R^(o))₂;—S(O)R^(o); —NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —C(═S)N(R^(o))₂;—C(═NH)—N(R^(o))₂; or —(CH₂)₀₋₂NHC(O)R^(o) wherein each independentoccurrence of R^(o) is selected from hydrogen, optionally substitutedC₁₋₆ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclicring, phenyl, —O(Ph), or —CH₂(Ph), or, notwithstanding the definitionabove, two independent occurrences of R^(o), on the same substituent ordifferent substituents, taken together with the atom(s) to which eachR^(o) group is bound, form a 3-8-membered cycloalkyl, heterocyclyl,aryl, or heteroaryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Optional substituents on the aliphaticgroup of R^(o) are selected from NH₂, NH(C₁₋₄aliphatic),N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂,CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), orhaloC₁₋₄aliphatic, wherein each of the foregoing C₁₋₄aliphatic groups ofR^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents. Suitable substituents on thesaturated carbon of an aliphatic or heteroaliphatic group, or of anon-aromatic heterocyclic ring are selected from those listed above forthe unsaturated carbon of an aryl or heteroaryl group and additionallyinclude the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*,═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphatic.Optional substituents on the aliphatic group of R* are selected fromNH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic,OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoingC₁₋₄aliphatic groups of R* is unsubstituted.

Optional substituents on the nitrogen of a non-aromatic heterocyclicring are selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph);optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring having one to four heteroatomsindependently selected from oxygen, nitrogen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form a 3-8-memberedcycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen,C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted.

The term “C₁₋₂₀alkylidene chain” refers to a straight or branched carbonchain of twenty carbon atoms or less that may be fully saturated or haveone or more units of unsaturation and has two points of attachment tothe rest of the molecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. For example, for compounds of formula I:

wherein Z is N or O, one of ordinary skill would recognize that asuitable tautomer is as depicted above. When the Z group of formula I isCH, one of ordinary skill would recognize that a suitable tautomer is asdepicted below:

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

3. Description of Exemplary Compounds

In certain embodiments, the present invention provides a compound offormula I wherein V is —S(O)₂—.

In other embodiments, the present invention provides a compound offormula I wherein V is —C(O)—.

In one embodiment, T is a C₁₋₆ straight or branched aliphatic chainwherein a methylene unit of T is optionally replaced by a C₃₋₆cycloaliphatic group.

Also preferred is a compound of formula I wherein Ring E is phenyl.

Also preferred is a compound of formula I wherein Ring E is naphthyl.

Also preferred is a compound of formula I wherein Ring E is pyridinyl.

Also preferred is a compound of formula I wherein Ring E is thienyl.

Also preferred is a compound of formula I wherein Ring E is furanyl.

Also preferred is a compound of formula I wherein Ring E is quinolinyl.

Also preferred is a compound of formula I wherein Ring E isbenzofuranyl.

Also preferred is a compound of formula I wherein Ring E is3,4-dihydro-2H-chromene.

Also preferred is a compound of formula I wherein Ring E is2,3-dihydrobenzo[b][1,4]dioxine.

According to one aspect, the present invention provides a compound offormula I, wherein Ring E is a preferred group as described above andsaid group is in combination with the remaining variables of formula Ias set forth in the classes and subclasses described herein.

In certain embodiments, each R^(A) of formula I, when present, isindependently R⁶, OR⁶, CN, or halo. In other embodiments, each R^(B) offormula I, when present, is independently OR⁶, N(R⁶)₂, NR⁶C(O)R⁶, halo,R⁶, C(O)R⁶, or NO₂.

In other embodiments, the A moiety of formula I, when present, is-T-NR⁶—, wherein T is a C₁₋₆ straight or branched aliphatic chain. SuchA moieties include —CH₂CH₂N(CH₃)—, —CH₂CH₂NH—, —CH₂NH—, and—CH₂CH(CH₃)NH—.

In certain embodiments, the present invention provides a compound offormula I wherein A is -T-NH— wherein T is a C₁₋₆ straight or branchedaliphatic chain wherein a methylene unit of T is replaced by a C₃₋₆cycloaliphatic group. Such cycloaliphatic groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups.In other embodiments, the Q moiety of formula I is a C₁₋₄ alkylidenechain wherein one methylene unit of Q is replaced by —O—, —NH—, or —S—.Such Q moieties of formula I include —CH₂CH₂O—, —CH₂O—, —OCH₂—,—OCH₂CH₂—, —CH(CH₃)O—, —NHCH₂—, —C(CH₃)₂O—, and —CH₂S—.

As described above, for compounds of the invention of Formula I, Z is O,N or C. Accordingly, in certain embodiments, where Z is N, thecorresponding compounds have the structure of Formula II:

In certain embodiments of Formula II, Y is hydrogen, Ring E is phenyl,and W is formula Ia, wherein V is —C(O)— as shown in Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein R^(A), r, A, Q,R^(B), and s are as defined above and herein.

Preferred is a compound of Formula IIa, wherein Q is a bond or a C₁₋₄alkylidene chain wherein one methylene unit of Q is replaced by —O—,—NH—, or —S—. Such Q moieties of formula IIa include —CH₂CH₂O—, —CH₂O—,—OCH₂—, —OCH₂CH₂—, —CH(CH₃)O—, —NHCH₂—, —C(CH₃)₂O—, and —CH₂S—.

Particularly preferred is a compound of Formula IIa, wherein Q is—CH₂O—.

Also particularly preferred is a compound of Formula IIa, wherein Q is—OCH₂—.

Also particularly preferred is a compound of Formula IIa, wherein Q is—NHCH₂—.

Also preferred is a compound of Formula IIa, wherein A is —C₁₋₆alkyl—NH—.

Particularly preferred is a compound of Formula IIa, wherein A is—CH₂CH₂NH—.

Also particularly preferred is a compound Formula IIa, wherein A is—CH₂NH—.

In certain embodiments, the present invention provides a compound offormula IIa, wherein A is —CH₂CH₂NH—, Q is —CH₂O—, and each R^(B) isindependently C₁₋₆ aliphatic, —CHO, or halogen. In other embodiments,the present invention provides a compound of formula IIb, wherein A is—CH₂CH₂NH—, Q is —CH₂O—, and each R^(B) is independently methyl, —CHO,fluoro, or chloro.

In other embodiments, the present invention provides a compound offormula IIa, wherein A is —CH₂CH₂NH—, Q is —CH═CH—, —CH₂O— or —NHCH₂ andeach R^(B) is independently CN, C₁₋₆ aliphatic, —N(R⁶)₂, or halogen.Such R^(B) groups include methyl, ethyl, butyl, isopropyl, chloro,fluoro, bromo, N(Me)₂, CF₃ and —CH₂-phenyl. According to anotherembodiment, the present invention provides a compound of formula IIawherein the benzo ring is substituted at one of, or both of, the C-4-and C-5 positions with tert-butyl, fluoro, or methyl.

According to another embodiment, the present invention provides acompound of formula IIa, wherein A is —CH₂CH₂NH— or —CH(CH₃)NH—, Q is—CH₂O— and each R^(B) is independently C₁₋₆ aliphatic, —N(R⁶)₂, —C(O)R⁶,or halogen. Such R^(B) groups include methyl, chloro, bromo, ethyl,N(Me)₂, —C≡CH and C(O)CH₃.

Yet another embodiment of the present invention relates to a compound offormula IIa, wherein A is —CH₂CH₂NH—, Q is —CH₂O—, —NHCH₂—, or—CH(CH₃)O—, and each R^(B) is independently C₁₋₆ aliphatic, —OR⁶, orhalogen. Such R^(B) groups include methyl, ethyl, —OMe, chloro, bromo,and fluoro.

According to still another embodiment, the present invention provides acompound of formula IIa, wherein A is —CH₂CH₂NH— or —CH₂CH(CH₃)NH—, Q is—CH₂O—, —NHCH₂—, —NH—, —CH(CH₃)O—, or —C(CH₃)₂O—, and each R^(B) isindependently C₁₋₆ aliphatic, —OR⁶, or halogen. Such R^(B) groupsinclude methyl, ethyl, —OMe, chloro, bromo, and fluoro. According toanother embodiment, the present invention provides a compound of formulaIIa wherein r is 2, each R^(A) is fluoro, and is present at the C-4- andC-5 positions.

In certain embodiments, the present invention provides a compound offormula IIa, wherein A is —CH₂CH₂NH—, Q is —CH₂O—, and each R^(B) isindependently C₁₋₆ aliphatic or halogen. In other embodiments, thepresent invention provides a compound of formula IIa, wherein A is—CH₂CH₂NH—, Q is —CH₂O—, and each R^(B) is independently methyl,isopropyl, fluoro, bromo, or chloro. In still other embodiments, thepresent invention provides a compound of formula IIa, wherein A is—CH₂CH₂NH—, Q is —CH₂O—, and each R^(B) is independently methyl, fluoro,or chloro. In yet other embodiments, the present invention provides acompound of formula IIa, wherein A is —CH₂CH₂NH—, Q is —CH₂O—, and eachR^(B) is independently methyl, bromo, or chloro.

Also preferred is a compound of Formula IIa, wherein A is

Also preferred is a compound of Formula IIa, wherein A is

Also preferred is a compound of Formula IIa, wherein A is

wherein U is —CH₂— or —CH₂CH₂—.

In certain embodiments of Formula II, Y is hydrogen, Ring E is phenyl, Wis Formula Ib and D is a bond, as shown below as formula IIb.

or a pharmaceutically acceptable salt thereof, wherein R^(A), r, R^(D),and s are as defined above and herein.

Preferred is a compound of Formula IIb, wherein R^(A) is R⁶ or halo. Incertain embodiments, R^(A) is methyl, chloro or bromo.

Particularly preferred is a compound of Formula IIb, wherein R^(A) ismethyl.

Also preferred is a compound of Formula IIb wherein R^(D) is halo, OR⁶,N(R⁶)₂, NR⁶C(O)R⁶, or two R^(D) are taken together to form amethylenedioxy or ethylenedioxy group. In certain embodiments, R^(D) is—OH, —N(Et)₂, —OMe, —NHC(O)CH₃, fluoro, or chloro.

According to another embodiment, the present invention provides acompound of formula III:

or a pharmaceutically acceptable salt thereof, wherein A, Q, R^(A), r,R^(B), and s are as defined above and herein.

In certain embodiments, each R^(A) of formula III, when present, isindependently R⁶, OR⁶, CN, or halo. In other embodiments, each R^(B) offormula III, when present, is independently OR⁶, N(R⁶)₂, NR⁶C(O)R⁶,halo, R⁶, C(O)R⁶, or NO₂. In other embodiments, the Q moiety of formulaIII is a C₁₋₄ alkylidene chain wherein one methylene unit of Q isreplaced by —O—, —NH—, or —S—. Such Q moieties of formula III include—CH₂CH₂O—, —CH₂O—, —OCH₂—, —OCH₂CH₂—, —CH(CH₃)O—, —NHCH₂—, —C(CH₃)₂O—,and —CH₂S—.

In other embodiments, the A moiety of formula III, when present, is-T-NR⁶—, wherein T is a C₁₋₆ straight or branched aliphatic chain. SuchA moieties include —CH₂CH₂N(CH₃)—, —CH₂CH₂NH—, —CH₂NH—, and—CH₂CH(CH₃)NH—.

In certain embodiments, the present invention provides a compound offormula III wherein A is -T-NH— wherein T is a C₁₋₆ straight or branchedaliphatic chain wherein a methylene unit of T is replaced by a C₃₋₆cycloaliphatic group. Such cycloaliphatic groups include cyclobutyl,cyclopentyl, and cyclohexyl groups.

According to another embodiment, the present invention provides acompound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein V, Q, R^(A), r,R^(B), n, and s are as defined above and herein.

In certain embodiments, each R^(A) of formula IV, when present, isindependently R⁶, OR⁶, CN, or halo. In other embodiments, each R^(B) offormula IV, when present, is independently OR⁶, N(R⁶)₂, NR⁶C(O)R⁶, halo,R⁶, C(O)R⁶, or NO₂.

In other embodiments, the Ring E group of formula IV is phenyl or a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 3-7 membered monocyclicheterocyclyl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Such Ring E groups of formula IV includepyridyl, thienyl, furyl, and pyrazolyl.

In still other embodiments, the Ring E group of formula IV is an 8-10membered bicyclic aryl ring or an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. Such Ring E groups of formula IV include naphthyl, quinolinyl,3,4-dihydro-2H-chromene, and 2,3-dihydrobenzo[b][1,4]dioxine.

In other embodiments, the Q moiety of formula IV is a C₁₋₄ alkylidenechain wherein one methylene unit of Q is replaced by —O—, —NH—, or —S—.Such Q moieties of formula IV include —CH₂CH₂O—, —CH₂O—, —OCH₂—,—OCH₂CH₂—, —CH(CH₃)O—, —NHCH₂—, —C(CH₃)₂O—, and —CH₂S—.

According to another aspect of the present invention, one of V and Q isa bond. According to yet another aspect of the present invention, bothof V and Q are a bond.

Representative compounds of formula I are set forth in Table 2 below.

TABLE 2 Representative Compounds of Formula I Cmpd # Compound 1

2

3

4

5

6

7

9

12

13

14

15

16

17

19

20

21

22

23

24

25

26

28

29

30

35

36

37

40

45

46

47

48

49

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

126

127

128

129

130

131

132

133

134

136

137

138

139

144

145

146

147

148

149

154

155

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

223

224

225

227

228

230

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

366

367

368

369

370

Although certain exemplary embodiments are depicted and described aboveand herein, it will be appreciated that a compounds of the invention canbe prepared according to the methods described generally above usingappropriate starting materials by methods generally available to one ofordinary skill in the art.

4. General Synthetic Methodology

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general schemes below, and the preparative examplesthat follow. Starting materials are commercially available from typicalchemical reagent supply companies, such as, Aldrich Chemicals Co., SigmaChemical Company and the like. Compounds that are not commerciallyavailable can be prepared by one of ordinary skill in art followingprocedures set forth in references such as, “Fieser and Fieser'sReagents for Organic Synthesis”, Volumes 1-15, John Wiley and Sons,1991; “Rodd's Chemistry of Carbon Compounds”, Volumes 1-5 andSupplementals, Elsevier Science Publishers, 1989; and “OrganicReactions”, Volumes 1-40, John Wiley and Sons, 1991.

Scheme 1

Scheme 1 teaches the general preparation of compounds of Formula I.Typically compounds of Formula I, where Y or W is

wherein A is —NH—, or —N(C₁₋₆alkyl)- are prepared by the coupling ofoptionally substituted compounds of Formula A, which has a nucleophilicfunction with optionally substituted compounds of Formula B, which havea terminal electrophilic functionality, such as a carboxylic acid,sulfonyl halide, isocyanate, or the like, as defined previously. Thesemethods are also applicable to compounds of Formulas II and III asdefined previously.

Synthetic Scheme 2a, 2b:

Scheme 2a teaches the preparation of optionally substitutedbenzimidazole compounds of Formula II. Scheme 2b teaches the preparationof additional optionally substituted benzimidazole compounds of formulaII.

An optionally substituted 1,2-diaminobenzene is reacted with anoptionally substituted carboxylic acid with a protected nucleophilicgroup to provide the benzimidazole intermediate, which is then cyclizedto form the benzimidazole moiety. The nucleophilic group is deprotectedand acylated, sulfonylated, carbamoylated, or alkylated to providecompounds of Formula II.Synthetic Scheme 3a, 3b, 3c:

Scheme 3a teaches the preparation of optionally substituted aryloxyacids. Optionally substituted aryloxy acids are prepared by reactingoptionally substituted phenolic compounds with optionally substitutedhalo-substituted alkyl esters (X is Cl, Br or I) to obtain thecorresponding ester.

The ester compound is then hydrolyzed to obtain a desired optionallysubstituted compound of Formula B.

As taught in Schemes 1, 2a, and 2b, compounds of Formula A and B arereacted together to obtain compounds of Formula I. For example, FormulaA as taught in Scheme 2b and Formula B as taught in the present Scheme3b can be reacted to form the corresponding compound of Formula I(Scheme 3c).

Synthetic Scheme 4:

Following the procedures taught in Schemes 1, 2a, 2b, 3a, 3b, and 3c,and using an optionally substituted aryl isocyanate compound of FormulaB,

optionally substituted compounds of Formula I are obtained.Synthetic Scheme 5:

Following the procedures taught in Schemes 1, 2a, 2b, 3a, 3b, and 3c,and using an optionally substituted aryl sulfonyl chloride compound ofFormula B,

optionally substituted compounds of Formula I are obtained.Synthetic Scheme 6:

Protected optionally substituted benzimidazoles of Formula A areprepared by reacting a starting cyano substituted benzimidazole with(Boc)₂O followed by reduction of the cyano group (Raney-Nickel/H₂ or thelike) to provide the desired compound of Formula A.

As taught previously in Schemes 1, 2a, 2b, 3a, 3b, 3c, 4 and 5,compounds of Formula A from the present Scheme 6 are derivatized toprovide the corresponding compounds of Formula I.Synthetic Schemes 7a, 7b:

An optionally substituted benzyl alcohol is reacted with phosgene toprovide an optionally substituted compound of Formula B.

This compound is then reacted with a compound of Formula A to providethe corresponding compound of Formula I. For example, where the compoundof Formula A is a benzimidazole taught in Scheme 2, the followingcompounds of Formula I, where s is 0 to 4, and m is 1 or 4, as itcorresponds to Q where Q is —O—C₁₋₄alkyl are obtained.

Synthetic Scheme 8:

A compound of Formula I, where W is

is prepared by reacting an optionally substituted di-amino benzene withan optionally substituted benzaldehyde or benzoic acid to obtain thecorresponding optionally substituted compound of Formula I, where R^(A),R^(D), r and t are as taught for Formula I, in a manner analogous toSchemes 2a and 2b.

Although certain exemplary embodiments are depicted and described aboveand herein, it will be appreciated that a compounds of the invention canbe prepared according to the methods described generally above usingappropriate starting materials by methods generally available to one ofordinary skill in the art.

5. Uses, Formulation and Administration

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome, orincontinence is provided comprising administering an effective amount ofa compound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof. In certain preferred embodiments,a method for the treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain is provided comprising administeringan effective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of one or more of acute, chronic,neuropathic, or inflammatory pain, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome, orincontinence.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels or calcium channels,preferably N-type calcium channels. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of NaV1.1,NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, orCaV2.2, and thus, without wishing to be bound by any particular theory,the compounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2, is implicated in a particular disease, condition, ordisorder, the disease, condition, or disorder may also be referred to asa “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2-mediated disease, condition or disorder” or a“CaV2.2-mediated condition or disorder”. Accordingly, in another aspect,the present invention provides a method for treating or lessening theseverity of a disease, condition, or disorder where activation orhyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the diseasestate.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.8. In other embodiments, compounds of theinvention are useful as inhibitors of NaV1.8 and CaV2.2. In still otherembodiments, compounds of the invention are useful as inhibitors ofCaV2.2.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Pharmaceutically Acceptable Compositions

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome, orincontinence is provided comprising administering an effective amount ofa compound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof. In certain preferred embodiments,a method for the treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain is provided comprising administeringan effective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of one or more of acute, chronic,neuropathic, or inflammatory pain, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome, orincontinence.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, epilepsyor epilepsy conditions, neurodegenerative disorders, psychiatricdisorders such as anxiety and depression, myotonia, arrhythmia, movementdisorders, neuroendocrine disorders, ataxia, multiple sclerosis,irritable bowel syndrome, or incontinence. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “patient”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,NaV1.9, or CaV2.2 and thus, without wishing to be bound by anyparticular theory, the compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder where activation or hyperactivity of one or more of NaV1.1,NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, orCaV2.2 is implicated in the disease, condition, or disorder. Whenactivation or hyperactivity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in a particulardisease, condition, or disorder, the disease, condition, or disorder mayalso be referred to as a “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2-mediated disease, condition ordisorder”. Accordingly, in another aspect, the present inventionprovides a method for treating or lessening the severity of a disease,condition, or disorder where activation or hyperactivity of one or moreof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9,or CaV2.2 may be assayed according to methods described generally in theExamples herein.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2activity in a biological sample or a patient, which method comprisesadministering to the patient, or contacting said biological sample witha compound of formula I or a composition comprising said compound. Theterm “biological sample”, as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof, and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful fora variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, the study ofsodium ion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Synthesis of Exemplary Compounds of the Invention Example 1

This example teaches the preparation of[2-(1-methyl-1H-benzoimidazol-2-yl)-ethyl]-carbamic acid tert-butylester (6). To a solution of beta-alanine (3.5 g, 18.5 mmol) and pyridine(3 mL, 37 mmol) in dichloromethane (20 mL) was added PFP ester (3.2 mL,18.5 mmol). After stirring at room temperature for 1 hour,1,2-phenyleneamine 1 (2 g, 18.5 mmol) in dichloromethane (20 mL) wasadded to the reaction mixture. After stirring overnight, the reactionwas quenched with water, extracted with dichloromethane (150 mL*2),dried and removed the solvent. Then the crude mixture was trituratedwith dichloromethane (20 mL), filtered to give white solid 2 as thedesired product (4.8 g) at 90% yield. LC/MS (10-99%) M+1/Z 280.3retention time 2.03 min.

Compound 2 (4 g) was dissolved in acetic acid (50 mL) and heated to 65°C. for 1 h, then cooled down to room temperature, removed the solvent invacuo. The residue was taken up with dichloromethane, quenched with satNaHCO₃, extracted with dichloromethane (150 mL) (pH=10), concentrated toafford 3 as light yellow solid (3.7 g) at 100% yield. LC/MS (10-99%)M+1/Z 262.2 retention time 2.30 min.

Compound 3 (3 g) was dissolved in 3 N HCl/EtOAC (50 mL/25 mL) andstirred at room temperature overnight. The solvent was in vacuo anddried in high vacuum to give compound 4 as pink solid (2.4 g) at greaterthan 95% yield. LC/MS (10-99%) M+1/Z 162.4 retention time 0.62 min.

To a solution of benzimidazole ethylene amine dihydrochloride (100 mg,0.43 mmol), 3,4-dimethylphenoxyacetic acid (77 mg, 0.43 mmol), and BOPreagent (190 mg, 0.43 mmol) in acetonitrile (5 mL) was addedtriethylamine (0.23 mL, 1.72 mmol). After stirring at room temperatureovernight, the solvent was removed under vacuum. The residue was takenup with water and saturated sodium bicarbonate (20 mL), extracted withdichloromethane (30 mL×2), dried and removed the solvent. The crudemixture was purified by using Gilson HPLC to give white solid 5 as a TFAsalt (170 mg) at 93% yield. MUX LC/MS (10-99%) M+1/Z 324.163 retentiontime 2.62 min; ¹H NMR (DMSO) δ 2.12 (s, 3H), δ 2.15 (s, 3H), δ 2.99 (t,2H, J=5.88 Hz), δ 3.59 (m, 2H), δ 4.40 (s, 2H), δ 6.64 (dd, 1H, J=2 Hz,6.5 Hz), δ 6.75 (d, 1H, J=1.8 Hz), δ 6.98 (6, 1H, J=6.6 Hz), δ 7.12 (m,2H), 7.40 (d, 1H, J=5.76 Hz), 7.53 (m, 1H), 8.30 (t, 1H, J=4.56 Hz),12.24 (s, 1H); ¹³C NMR (DMSO) δ 18.4, δ 19.57, δ 28.58, δ 36.74, δ67.07, δ 110.8, δ 111.58, δ 116.13, δ 118.12, δ 120.86, δ 121.52, δ128.70, δ 130.12, δ 134.21, δ 137.25, δ 143.24, δ 152.74, δ 155.73, δ167.85.

Boc-protected benzimidazole ethyl amine 3 (400 mg, 1.53 mmol) wasdissolved in THF (50 mL) and cooled to 0° C. under nitrogen, followed bydropwise addition of LiHMDS (535 mg, 3.37 mmol) in THF (10 mL) viasyringe. The mixture was warmed to room temperature and stirred for 20min. Methyl iodide (0.1 mL, 1.68 mmol) was added dropwise to thereaction mixture. After stirring for 5 h at room temperature, thereaction was quenched with water (20 mL) and extracted with EtOAc (30mL×2), dried, concentrated and purified by ISCO flash chromatography.

Example 2

This example teaches the preparation of[2-(1H-benzoimidazol-2-yl)-ethyl]-carbamic acid 3,4-dimethyl-benzylester. To a solution of 3,4-dimethylbenzyl alcohol (1.5 g, 11.0 mmol) intoluene (20 mL) was added phosgene (13 mL, 24.3 mmol, 20% in toluene).After stirring at room temperature overnight, excess phosgene andtoluene was removed in vacuo, and dried under high vacuum for 2 h.providing 3,4-dimethylbenzylchloroformate (1.8 g) as an oil at 80%yield. (reference: Nägele, E.; Schelhaas, M.; Kuder, N.; Waldmann, H. J.Am. Chem. Soc. 1998, 120, 6889)

Example 3

This example teaches the preparation of1-[2-(1H-benzoimidazol-2-yl)-ethyl]-3-(3,4-dichloro-benzyl)-urea. To asolution of benzimidazole ethyl amine dihydrochloride (50 mg, 0.21 mmol)in pyridine (1.5 mL) was added 3,4-dichlorobenzylisocyanate (43 μL, 0.21mmol). After stirring overnight at room temperature, the crude mixturewas purified by Gilson HPLC to afford white solid (50 mg) as a TFA saltat 92% yield. LC/MS (10-99%) M+1/Z 324.2 retention time 2.97 min.

Example 4

This example teaches the preparation ofN-[2-(1H-Benzoimidazol-2-yl)-ethyl]-3,4-dichloro-benzenesulfonamide. Toa solution of benzimidazole ethyl amine dihydrochloride (50 mg, 0.21mmol) in pyridine (1.5 mL) was added 3,4-dichlorobenzylisocyanate (58μL, 0.21 mmol). After stirring overnight at room temperature, the crudemixture was purified by Gilson HPLC to afford white solid (55 mg) as TFAsalt at 92% yield.

Example 5

This example teaches the preparation of2-(2,6-Difluoro-phenyl)-7-methyl-1H-benzoimidazole according to thefollowing procedure. A solution of 3-methyl-benzene-1,2-diamine (100 mg,0.82 mmol) and 2,6-difluorobenzaldehyde in EtOH (2 mL) was heated for 5min at 180° C. in a microwave synthesizer. The EtOH was removed, theresidue was dissolved in DMSO (1 mL), and was purified on a Gilson HPLCto afford 2-(2,6-difluoro-phenyl)-7-methyl-1H-benzoimidazole as TFA salt(200 mg) at 100% yield. MUX LC/MS (10-99%) M+1/Z 245.061 retention time2.1 min.

Other compounds of Formula I have been prepared by methods substantiallysimilar to those described above. The characterization data for thesecompounds is summarized in Table 3 below. The compound numberscorrespond to the compound numbers listed in Table 2.

TABLE 3 Characterization Data for Selected Compounds of Formula I fromTable 2 LC/MS LC/RT Cmpd # M+ (min) 3 256.28 3.20 14 336.40 2.63 16326.20 1.90 23 324.40 3.74 49 326.20 2.75 54 344.00 2.94 66 372.20 2.46165 324.20 1.84 171 364.00 2.32 189 324.20 1.69 192 324.20 2.79 196358.20 2.45 197 332.00 2.87 199 321.20 1.85 249 309.20 2.06 250 314.002.76 251 313.20 1.91 252 329.20 1.97 253 309.20 1.96 254 363.20 2.17 255364.00 2.25 256 365.20 2.19 257 379.20 2.35 258 364.00 2.25 259 339.202.14 260 372.20 2.15 261 372.20 2.09 262 386.00 2.22 263 372.20 2.07 264346.20 2.04 265 338.20 3.13 266 344.20 3.00 267 323.20 2.89 268 370.002.89 269 336.40 2.08 270 344.00 3.90 271 346.00 3.70 272 340.00 3.63 273324.00 3.81 274 325.20 3.18 275 366.82 3.20 276 346.20 3.30 277 315.783.10 278 267.30 3.30 279 346.85 3.30 280 335.30 3.10 281 326.43 3.50 282284.33 3.50 283 323.41 3.10 284 317.36 3.10 285 321.20 1.88 286 339.201.76 287 354.20 2.28 288 353.20 1.55 289 366.20 2.16 290 350.20 2.06 291382.00 2.96 292 372.00 2.84 293 372.00 3.07 294 332.00 2.75 295 338.202.62 296 348.00 2.90 297 373.00 2.66 298 384.00 2.85 299 400.20 3.00 300384.00 2.77 301 413.00 3.10 302 358.00 3.09 303 356.20 2.96 304 400.202.29 305 352.20 1.68 306 398.20 2.44 307 380.00 2.35 308 320.20 2.11 309398.20 1.88 310 321.20 1.90 311 332.20 2.01 312 338.20 1.90 313 380.002.37 314 388.20 2.49 315 386.20 2.52 316 422.00 2.46 317 381.00 2.01 318386.20 2.57 319 388.20 2.23 320 381.40 1.68 321 388.20 2.34 322 386.202.69 323 408.20 2.34 324 328.20 2.15 325 401.20 2.10 326 372.20 2.42 327400.20 2.26 328 398.00 2.43 329 347.20 1.30 330 338.20 1.81 331 347.201.26 332 381.40 1.61 333 353.20 1.74 334 335.40 1.63 335 335.20 1.86 336383.20 1.73 337 374.20 1.65 338 339.00 1.46 339 408.40 1.44 340 347.201.44 341 381.40 1.53 342 415.20 2.15 343 364.40 1.79 344 388.20 2.39 345362.20 2.27 346 342.20 2.26 347 421.00 2.05 348 350.20 2.13 349 376.002.31 350 382.00 2.23 351 404.40 2.46 352 376.00 2.37 353 406.20 2.26 354404.20 2.63 355 328.00 2.06 356 342.00 1.82 357 344.00 1.87 358 350.202.02 359 350.20 1.89 360 350.20 1.98 361 368.00 1.96 362 366.00 1.99 363350.20 2.08 366 334.00 2.54 367 350.20 2.75 368 316.20 2.45 369 330.202.68 370 344.00 2.83 Micromass MUX LCT 4 channel LC/MS, Waters 60 Fpump, Gilson 215 4 probe autosampler, Gilson 849 injection module, 1.5mL/min/column flow rate, 10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)gradient, Phenomenex Luna 5u C18 columns (50 × 4.60 mm), Waters MUXUV-2488 UV detector, Cedex 75 ELSD detectors.Assays for Detecting and Measuring NaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (See,Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69 (4): 1272-80,and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4 (4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with ChemicalStimulation Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed    twice with 225 μL of Bath Solution #2 (BS #2).-   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin    stock solution with 10% Pluronic 127 1:1 and then dissolving the mix    in the appropriate volume of BS #2.-   3) After bath solution is removed from the 96-well plates, the cells    are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated    in the dark for 30 minutes at room temperature.-   4) While the cells are being stained with coumarin, a 15 μL oxonol    solution in BS #2 is prepared. In addition to DiSBAC₂(3), this    solution should contain 0.75 mM ABSC1 and 30 μL veratridine    (prepared from 10 mM EtOH stock, Sigma #V-5754).-   5) After 30 minutes, CC2-DMPE is removed and the cells are washed    twice with 225 μL of BS #2. As before, the residual volume should be    40 μL.-   6) Upon removing the bath, the cells are loaded with 80 μL of the    DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,    is added to achieve the desired test concentration to each well from    the drug addition plate and mixed thoroughly. The volume in the well    should be roughly 121 μL. The cells are then incubated for 20-30    minutes.-   7) Once the incubation is complete, the cells are ready to be    assayed on VIPR® with a sodium addback protocol. 120 μL of Bath    solution #1 is added to stimulate the NaV dependent depolarization.    200 μL tetracaine was used as an antagonist positive control for    block of the NaV channel.    Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus

=R_(f)/R_(i) is then calculated. For the Na⁺ addback analysis timewindows, baseline is 2-7 sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound

Solutions [mM] Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1,HEPES 10, pH 7.4 with NaOH Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂1, HEPES 10, pH 7.4 with KOH (final K concentration~5 mM) CC2-DMPE:prepared as a 5 mM stock solution in DMSO and stored at −20° C.DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at roomtemperatureCell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

C) VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method #2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂0

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a10 μM final staining concentration. The cells are stained for 30 minutesin the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The requiredamount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixedwith 1 μL 10% pluronic for each mL of solution to be made and vortexedtogether. Then HBSS/HEPES is added to make up 2× solution. Finally, theABSC1 is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the2×DiSBAC₂(3) w/ ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay Buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.40, 330 mOsm

Pluronic stock (1100×): 100 mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO

Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO

ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

-   -   1. Insert or use electrodes into each well to be assayed.    -   2. Use the current-controlled amplifier to deliver stimulation        wave pulses for 3 s. Two seconds of pre-stimulus recording are        performed to obtain the un-stimulated intensities. Five seconds        of post-stimulation recording are performed to examine the        relaxation to the resting state.        Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus

=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

CURRENT-CLAMP Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filledwith (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

Assays for Detecting and Measuring CaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying CaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedcalcium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the CaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with electrical means to evoke a CaV dependent membranepotential change from unblocked channels, which was detected andmeasured with trans-membrane potential-sensitive dyes. Antagonists weredetected as a decreased membrane potential response to the stimulus. Theoptical membrane potential assay utilized voltage-sensitive FRET sensorsdescribed by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien(1995) “Voltage sensing by fluorescence resonance energy transfer insingle cells” Biophys J 69 (4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4 (4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4 (9): 431-439).

VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how CaV2.2 inhibition activity ismeasured using the optical membrane potential method. Other subtypes areperformed in an analogous mode in a cell line expressing the CaV ofinterest.

HEK293 cells stably expressing CaV2.2 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM Acid Yellow 17 (Aurora #VABSC) in H₂O

370 mM Barium Chloride (Sigma Cat# B6394) in H₂O

Bath X

160 mM NaCl (Sigma Cat# S-9888)

4.5 mM KCl (Sigma Cat# P-5405)

1 mM MgCl2 (Fluka Cat# 63064)

10 mM HEPES (Sigma Cat# H-4034)

pH 7.4 using NaOH

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is added to wells containing washed cells, resultingin a 10 μM final staining concentration. The cells are stained for 30minutes in the dark at RT.

2×CC2DMPE & DISBAC₆(3)=8 μM CC2DMPE & 2.5 μM DISBAC₆(3): Vortex togetherboth dyes with an equivalent volume of 10% pluronic (in DMSO). Vortex inrequired amount of Bath X with beta-cyclodextrin. Each 96 well cellplate will require 5 ml of 2×CC2DMPE. Wash plate with ELx405 with BathX, leaving a residual volume of 50 μL/well. Add 50 μL of 2×CC2DMPE &DISBAC₆(3) to each well. Stain for 30 minutes in the dark at RT.

1.5×AY17=750 μM AY17 with 15 mM BaCl₂: Add Acid Yellow 17 to vesselcontaining Bath X. Mix well. Allow solution to sit for 10 minutes.Slowly mix in 370 mM BaCl₂. This solution can be used to solvatecompound plates. Note that compound plates are made at 1.5× drugconcentration and not the usual 2×. Wash CC2 stained plate, again,leaving residual volume of 50 μL. Add 100 uL/well of the AY17 solution.Stain for 15 minutes in the dark at RT. Run plate on the optical reader.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Assay Protocol

Insert or use electrodes into each well to be assayed.

Use the current-controlled amplifier to deliver stimulation wave pulsesfor 3-5 s. Two seconds of pre-stimulus recording are performed to obtainthe un-stimulated intensities. Five seconds of post-stimulationrecording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus

=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such asmibefradil, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for CaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy of calciumchannel blockers expressed in HEK293 cells. HEK293 cells expressingCaV2.2 have been visually identified and probed with fine tip glasselectrodes connected to an amplifier (Axon Instruments). The “voltageclamp” mode has been used to assess the compound's IC50 holding thecells at −100 mV. The results of these experiments have contributed tothe definition of the efficacy profile of the compounds.

VOLTAGE-CLAMP Assay in HEK293 Cells Expressing CaV2.2

CaV2.2 calcium currents were recorded from HEK293 cells using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +20 mV for 50 ms at frequencies of 0.1,1, 5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau beforeproceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), BaCl₂ (10), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10).

Following these procedures, representative compounds of the presentinvention were found to possess desired N-type calcium channelmodulation activity.

Compounds of the invention as shown in Table 2 were found modulatevoltage-gated sodium channels at 25.0 μM or less.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

1. A method of treating or lessening the severity of a disease,disorder, or condition selected from acute, chronic, neuropathic, orinflammatory pain comprising the step of administering to a patient aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: r is 0; Z is N;Y is hydrogen; W is Formula Ia:

wherein: A is -T-NH—, wherein: T is —CH₂CH₂—; V is —C(O)—; Q is —CH₂O—;m is 1; Ring E is phenyl; s is 0 to 1; each occurrence of R isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group; and R^(B) is selected from J wherein: J is halo, CN,NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸,C(O)OH, C(O)OR⁶ or OR⁶; or: two J on adjacent ring atoms, takentogether, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R⁶ is hydrogenor a C₁₋₆aliphatic group substituted with R⁷, wherein: R⁷ is aC₃₋₈cycloaliphatic, C₆₋₁₀ aryl, a 5-10 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or a 3-10 membered heterocyclyl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R⁷ isoptionally substituted with up to two substituents independentlyselected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH₂)_(n)-G,wherein n is 0 or 1; and wherein G is selected from halo, CN, NO₂, CF₃,OCF₃, OH, S-aliphatic, S(O)-aliphatic, SO₂-aliphatic, NH₂, N-aliphatic,N(aliphatic)₂, N(aliphatic)R⁸, COOH, C(O)O(-aliphatic, or O-aliphatic;and R⁸ is an amino protecting group.
 2. The method according to claim 1,wherein the disease, condition, or disorder is femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; neuropathic low back pain;myofascial pain syndrome; fibromyalgia; temporomandibular joint pain;chronic visceral pain, including, abdominal; pancreatic; IBS pain;chronic headache pain; migraine; tension headache, including, clusterheadaches; chronic neuropathic pain, including, post-herpetic neuralgia;diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain, including, sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; interstitial cyctitis (IC);or prostatitis; arthritis, migraine cluster headaches, trigeminalneuralgia, herpetic neuralgia or general neuralgias.
 3. The methodaccording to claim 1, wherein each R^(B) is independently OR⁶, N(R⁶)₂,halo, or NO₂.
 4. The method according to claim 1, wherein said compoundis of formula IIa:

or a pharmaceutically acceptable salt thereof.
 5. The method accordingto claim 4, wherein: A is —CH₂CH₂NH—; Q is —CH₂O—; and each R^(B) isindependently halogen.
 6. The method according to claim 4, wherein: A is—CH₂CH₂NH—; Q is —CH₂O—; and each R^(B) is independently CN, —N(R⁶)₂, orhalogen.
 7. The method according to claim 4, wherein: A is —CH₂CH₂NH—; Qis —CH₂O—; and each R^(B) is independently —N(R⁶)₂, or halogen.
 8. Themethod according to claim 4, wherein: A is —CH₂CH₂NH—; Q is —CH₂O—; andeach R^(B) is independently —OR⁶, or halogen.
 9. The method according toclaim 4, wherein: A is —CH₂CH₂NH—; Q is —CH₂O—; and each R^(B) isindependently fluoro, or chloro.
 10. The method according to claim 4,wherein: A is —CH₂CH₂NH—; Q is —CH₂O—; and each R^(B) is independentlybromo, or chloro.
 11. The method according to claim 1, wherein saidmethod comprises the step of administering to said patient an effectiveamount of a compound selected from any one of the following:


12. A method of inhibiting NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.7, orNaV1.8 activity in a biological sample which method comprises contactingsaid biological sample with a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: r is 0; Z is N;Y is hydrogen; W is Formula Ia:

wherein: A is -T-NH—, wherein: T is —CH₂CH₂—; V is —C(O)—; Q is —CH₂O—;m is 1; Ring E is phenyl; s is 0 to 1; each occurrence of R isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group; and R^(B) is selected from J wherein: J is halo, CN,NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸,C(O)OH, C(O)OR⁶ or OR⁶; or: two J on adjacent ring atoms, takentogether, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R⁶ is hydrogenor a C₁₋₆aliphatic group substituted with R⁷, wherein: R⁷ is aC₃₋₈cycloaliphatic, C₆₋₁₀ aryl, a 5-10 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or a 3-10 membered heterocyclyl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R⁷ isoptionally substituted with up to two substituents independentlyselected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH₂)_(n)-G,wherein n is 0 or 1; and wherein G is selected from halo, CN, NO₂, CF₃,OCF₃, OH, S-aliphatic, S(O)-aliphatic, SO₂-aliphatic, NH₂, N-aliphatic,N(aliphatic)₂, N(aliphatic)R⁸, COOH, C(O)O(-aliphatic, or O-aliphatic;and R⁸ is an amino protecting group.
 13. A method of inhibiting NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.7, or NaV1.8 activity in a patient to treator lessen the severity of a disease, disorder or condition in saidpatient wherein said disease, disorder or condition is selected fromacute, chronic, neuropathic or inflammatory pain, and wherein saidmethod comprises administering to said patient a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: r is 0; Z is N;Y is hydrogen; W is Formula Ia:

wherein: A is -T-NH—, wherein: T is —CH₂CH₂—; V is —C(O)—; Q is —CH₂O—;m is 1; Ring E is phenyl; s is 0 to 1; each occurrence of R isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group; and R^(B) is selected from J wherein: J is halo, CN,NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸,C(O)OH, C(O)OR⁶ or OR⁶; or: two J on adjacent ring atoms, takentogether, form 1,2-methylenedioxy or 1,2-ethylenedioxy; R⁶ is hydrogenor a C₁₋₆aliphatic group substituted with R⁷, wherein: R⁷ is aC₃₋₈cycloaliphatic, C₆₋₁₀ aryl, a 5-10 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or a 3-10 membered heterocyclyl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R⁷ isoptionally substituted with up to two substituents independentlyselected from R, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH₂)_(n)-G,wherein n is 0 or 1; and wherein G is selected from halo, CN, NO₂, CF₃,OCF₃, OH, S-aliphatic, S(O)-aliphatic, SO₂-aliphatic, NH₂, N-aliphatic,N(aliphatic)₂, N(aliphatic)R⁸, COOH, C(O)O(-aliphatic, or O-aliphatic;and R⁸ is an amino protecting group.
 14. The method according to claim13, wherein R^(B) is OR⁶, N(R⁶)₂, halo, or NO₂.
 15. The method accordingto claim 13, wherein said compound is of formula IIa:

or a pharmaceutically acceptable salt thereof.
 16. The method accordingto claim 15, wherein: A is —CH₂CH₂NH—; Q is —CH₂O—; and R^(B) is CN,—N(R⁶)₂, —OR⁶ or halogen.
 17. The method according to claim 16, wherein:R^(B) is —N(R⁶)₂, or halogen.
 18. The method according to claim 17,wherein: R^(B) is fluoro, chloro or bromo.
 19. The method according toclaim 18, wherein: R^(B) is bromo or chloro.
 20. The method according toclaim 13, wherein said method comprises administering to said patient acompound selected from any one of the following: